systematic empirical vs. test-guided anti-tb treatment impact in severely immunosuppressed hiv-infected adults initiating art with cd4 cell counts <100/mm3

Conditions: HIV-1 Infection

Summary: in countries with a high tuberculosis (tb) prevalence, tb and invasive bacterial infections are leading causes of early death in patients who initiate antiretroviral therapy (art) with advanced immunodeficiency. we hypothesize that a systematic 6-month empirical tb treatment initiated 2 weeks before the introduction of art in hiv-infected adults with severe immunosuppression (cd4\<100/mm3) and no overt evidence of tb will reduce the risk of death and invasive bacterial infections. this strategy will be compared to one of extensive tb testing using point-of-care tests (xpert mtb/rif® and urine lipoarabinomanan lam) and chest x-ray to identify and treat only patients with at least one positive test suggestive of tb.

settings: cambodia, côte d'ivoire, uganda, vietnam. design: multicentre, two-arm, unblinded randomized controlled superiority trial. objective: to compare the 24-week risk of death and occurrence of invasive bacterial infection between two experimental strategies in hiv-1 infected adults who start art with a cd4 count \<100/mm3: (i) continuous extensive tb screening during follow-up each time the patient present with symptoms, versus (ii) systematic empirical tb treatment started 2 weeks before art initiation. trial strategies: at inclusion, participants will be randomized 1:1 in two strategies of tb testing and treatment: extensive tb screening, or systematic empirical tb treatment. extensive tb screening (arm 1): in this arm: * tb screening point-of-care tests (xpert mtb/rif®, urine lam) and chest x-ray will be used extensively at randomisation (in all patients) and during follow-up (in patients with signs or symptoms suggestive of tb); * only patients who meet standardized criteria for tb at inclusion or during follow-up will receive a standard tb treatment (2erhz/4rh); * art (tenofovir(tdf)-lamivudine (3tc)/emtricitabine(ftc) or zidovudine (azt)-lamivudine+ efavirenz) will be started immediately after randomization in patients not put on tb treatment, and 2 weeks after initiation of tb treatment in others. systematic empirical tb treatment (arm 2): in this arm: * tb screening point-of-care tests will not be used; * all patients will start a 6-month standard tb treatment (2erhz/4rh) at randomization; art (tenofovir-lamivudine/emtricitabine or zidovudine-lamivudine+ efavirenz) will be started 2 weeks after tb treatment initiation. both strategies will apply to the first 24 weeks in the trial (intervention period). from week-24 to week-48, the choice of tb tests and the prescription of tb treatment will be left upon the decision of the investigator in both trial arms. inclusion time: 24 months. follow-up: each patient will be followed 48 weeks. statistical analysis: the primary analysis will be intention to treat. it will compare the 24-week probability of death or invasive bacterial infection between arms. sample size: 1050 participants. this will allow demonstration of a 40% reduction in the 24-week probability of death or invasive bacterial infection in arm 2, compared to arm 1 (α 5%; 1-β 80%).

Eligibility criteria:
inclusion criteria: * age ≥18 years; * hiv-1 infection as documented at any time prior to trial entry, as per national testing procedures; * cd4 \<100 cells/mm3; * no history of antiretroviral drug use (except transient art for pmtct); * able to correctly understand the trial and to sign the informed consent. exclusion criteria: * hiv-2 co-infection; * contra-indication to efavirenz; * aspartate aminotransferase (ast) or alanine aminotransferase (alt) \>5 times the upper limit of normal; * creatinine clearance \<50 ml/min; * overt evidence that tb treatment should be started immediately; * history of tb treatment in the past 5 years; * ongoing tb chemoprophylaxis (isoniazid preventive therapy); * any condition that would lead to differ art initiation (e.g. acute condition requiring investigations and/or treatment prior to art initiation); * current pregnancy or breastfeeding.

Keywords: hiv-1 tuberculosis systematic empiric tb treatment art tb diagnosis xpert mtb/rif® urine lam